JP2012255013A - Selective crystallization of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium as hemipentahydrate or monohydrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide crystallization procedures which yield the hemipentahydrate form or the monohydrate form.SOLUTION: The present invention discloses 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid sodium hemipentahydrate and monohydrate, and methods of preparing the hemipentahydrate or monohydrate through control of the nucleation temperature and rate of crystallization.

Description

  The present invention relates to sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate and monohydrate, a composition containing the 2.5 hydrate and / or monohydrate. And a method for selectively crystallizing the 2.5 hydrate or monohydrate.

(Cross-reference)
This application claims priority from provisional application No. 60 / 179,505, filed Feb. 1, 2000, under US Patent Act (35 USC) 119 (e).
This application is a divisional application based on Japanese Patent Application No. 2010-30081, which is a divisional application based on Japanese Patent Application No. 2001-556833 .

    It has been proposed to use bisphospohnates such as 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid (risedronate (RISEDRONATE)) for the treatment of diseases of bone and calcium metabolism. These diseases include osteoporosis, hyperparathyroidism, malignant hypercalcemia, osteolytic metastases, progressive ossifying myositis, generalized calcification, arthritis, neuritis, bursitis, Tendinitis and other inflammatory diseases are included. Paget's disease and ectopic bone formation are now successfully treated using EHDP (ethane-1-hydroxy-1,1-diphosphonic acid) and risedronate together.

  Bisphosphonates tend to inhibit bone tissue resorption, which is beneficial for patients suffering from excessive bone loss. However, despite some similarities in biological activity, not all bisphosphonates exhibit the same degree of biological activity. Some bisphosphonates have serious drawbacks with regard to the degree of toxicity in animals and tolerance or negative side effects in humans. The salt and hydrate forms of bisphosphonates change both their solubility and bioavailability.

  Certain bisphosphonic acids and their salts can form hydrates, and risedronate sodium exists in three hydration states: 1 hydrate, 2.5 hydrate, and anhydride It is known from the literature.

US Pat. No. 5,583,122 (Benedict et al., Procter & Gamble Co., issued December 10, 1996) International Publication No. 97/29754 Pamphlet European Patent No. 0,407,344 International Publication No. 97/44017 Pamphlet US Pat. No. 5,730,715 European Patent No. 0,407,345

"An American Conference, Bisphosphonates: Current Status and future Prospects" (UK Medical Association, London, UK, May 21-22, 1990, established by IBC Technical Services) “Remington's Pharmaceutical Sciences” (18th Edition, Mack Publishing Company, 1990, pp. 1288-1300) "Handbook of Pharmaceutical Excipients" (2nd edition, pages 126-134, 1994, the American Pharmaceutical Association & the Pharmaceutical Press)

  Crystallization procedures that selectively produce the 2.5 hydrate form or the monohydrate form are desirable.

  In this application, 2.5 hydrate and monohydrate crystal forms, compositions containing 2.5 hydrate and monohydrate crystal forms, and selective formation of these crystal forms are described. Describe.

  The present invention relates to sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate and monohydrate, a composition containing the 2.5 hydrate and / or monohydrate. And a method for selectively crystallizing the 2.5 hydrate or monohydrate. Nucleation temperature and crystallization rate are important variables that control the proportion of hydrate formed.

(Detailed Description of the Invention)
The present invention relates to sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate and monohydrate, and a composition containing the 2.5 hydrate and monohydrate. To target. Also new methods for selectively crystallizing geminal bisphosphonate, risedronate sodium, sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate as 2.5 hydrate and monohydrate. Disclose.

Risedronate Sodium Risedronate sodium, the monosodium salt of risedronate, exists in three crystalline hydrate states: anhydrous, monohydrate, and 2.5 hydrate. Monohydrate and 2.5 hydrate are preferred.

  The 2.5 hydrate is the thermodynamically preferred crystalline form under typical processing conditions, which is based on the observation that the monohydrate crystals have been converted to the 2.5 hydrate form.

  The monohydrate is present at about 5.0% to about 7.1% by weight, more preferably about 5.6% to about 6.5%, and most preferably about 5.6% water. Monohydrate is further characterized by single crystal X-ray crystal diffraction and thermogravimetric analysis. In addition, the monohydrate form exhibits distinguishable characteristics when investigated by X-ray powder diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, or near infrared spectroscopy.

  The 2.5 hydrate is present by weight from about 11.9% to about 13.9%, more preferably from about 12.5% to about 13.2%, most preferably about 12.9% water. . The 2.5 hydrate is further characterized by single crystal X-ray crystal diffraction and thermogravimetric analysis. In addition, the form of 2.5 hydrate exhibits distinguishable characteristics when investigated by X-ray powder diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, or near infrared spectroscopy.

  Nucleation temperature and crystallization rate are important variables that control the proportion of hydrate formed. The nucleation temperature can be controlled by controlling the water to solute ratio, the solution temperature, and the organic solvent to water ratio.

  Risedronate sodium 2.5 hydrate is the thermodynamically preferred form under the typical processing conditions described herein. The composition is about 50% to about 100% by weight of risedronate sodium hydrate, more preferably about 80% to about 100%, most preferably about 90% to about 100% risedronate sodium 2.5 water. And about 50% to about 0%, more preferably about 20% to about 0%, and most preferably about 10% to about 0% risedronate sodium monohydrate.

  By changing the processing conditions as described herein, a monohydrate crystal form can be selectively generated. The composition comprises about 50% to about 99%, more preferably about 80% to about 99%, most preferably about 95% to about 99% risedronate sodium monohydrate by weight of risedronate sodium hydrate. And about 50% to about 1%, more preferably about 20% to about 1%, and most preferably about 5% to about 1% risedronate sodium 2.5 hydrate.

  The present invention further includes pharmaceutical compositions containing 2.5 hydrated and monohydrated compounds.

Definitions and Usage of Terms The following list is a definition of terms used herein.
The term “risedronate” as used herein means 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid and has the following structure:

  The risedronate of the compound is further described in US Pat.

  A “solvent” as used herein is a substance that can dissolve other substances to form a homogeneous solution. The solvent may be either polar or nonpolar. The solvent is selected from the group consisting of alcohol, ester, ether, ketone, amide, nitrile. Most preferred is isopropanol.

Method The method according to the invention is characterized in that the method described herein is easily adapted for industrial production. The following non-limiting examples illustrate the method of the present invention.

  The amount of hydration of sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate can be controlled by changing the crystallization parameters that control the nucleation temperature and crystallization rate. The ratio of crystal form of 2.5 hydrate to monohydrate in the product is determined by the ratio of water to sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate, and the ratio of isopropanol to water temperature. It is possible to effectively control by changing the same as (see below).

General Method An aqueous solution of 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate sodium is 0 to 75 ° C., preferably 25 to 75 ° C., more preferably 45 to 75 ° C., depending on the crystallization conditions. Thus, it is thought to selectively produce either the monohydrate or the 2.5 hydrate crystal form. Nucleation temperature and crystallization rate control the hydrate, the ratio of water to isopropanol, and the ratio of hydrate state formed by changing the temperature and cooling ramps of the aqueous solution and cooling. To control.

  Table 1 shows eight examples of reaction conditions that selectively produce sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate that also includes changing the ratio of 2.5 hydrate to monohydrate. Show. The theoretical water content is 5.6% for monohydrate and 12.9% for 2.5 hydrate.

Example 1 2.5 Hydrate Cool with a nucleation condition of 25-70 ° C, preferably 50-70 ° C, and a gradient of 0.1-5 ° C / min, preferably 0.1-2 ° C / min. This produces 2.5 hydrate. 3-Pyridyl-1-hydroxyethylidene-1,1-bisphosphonic acid is suspended in water at about 60 ° C., pH is adjusted to 4.7 to 5.0 with sodium hydroxide, and isopropanol is added to the resulting solution. In addition, the suspension is cooled and the product is filtered and collected to produce the 2.5 hydrate.

Example 2 Monohydrate Nucleation conditions of about 45 ° C. or higher, preferably about 55 ° C. or higher, and holding at this temperature for an appropriate time, without cooling or rapidly cooling the monohydrate Generate. When an aqueous solution of sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate is maintained at 70 ° C., the monohydrate gradually crystallizes, and the crystals are isolated from this hot solution by filtration. In contrast, crystalline monohydrate is obtained by directly cooling an aqueous solution at 70 ° C. in isopropanol at 0 ° C.

Compositions The compounds made herein can be used in pharmaceutical compositions. The term “pharmaceutical composition” means a dosage form composed of a safe and effective amount of an active ingredient and a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein comprise from about 0.1 to about 99%, preferably from about 0.5 to about 95% of the bisphosphonate active ingredient, and from about 1 to about 99.9%, preferably 5.00. ~ 99.90% pharmaceutically acceptable excipients. For risedronate sodium monohydrate or 2.5 hydrate, the oral composition is preferably 0.25 to 40%, preferably about 0.5 to about 30% risedronate active ingredient, and about 60 to about 97%, preferably about 70 to about 99.5% of pharmaceutically acceptable excipients.

  The term “safe and effective amount” as used herein is sufficiently high but serious enough that the condition and / or condition being treated is clearly improved within the scope of appropriate medical judgment. Means the amount of the compound or composition low enough (with reasonable benefit / risk ratio) so as not to cause any side effects. The safe and effective amounts of active ingredients used in the methods of the invention herein are the specific condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the combination therapy It will vary depending on the nature, the particular active ingredient used, the particular pharmaceutically acceptable excipient utilized, and similar factors within the knowledge and experience of the treating physician.

  The term “risedronate active ingredient” includes risedronate, a risedronate salt, an ester of risedronate, or a mixture thereof. Any pharmaceutically acceptable non-toxic risedronate salt or ester can be used as the risedronate active ingredient in the dosage form of the present invention. The risedronate salt may be an acid addition salt, particularly the hydrochloride for risedronate. However, any non-toxic organic acid or inorganic acid salt acceptable as a pharmaceutical can be used. Furthermore, salts formed with a phosphonic acid group as a partner can also be used. It includes, but is not limited to, alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg). Preferred salts are Ca salt and Na salt.

Other esters of bisphosphonates particularly suitable for use as active ingredients herein include linear or branched C ₁ -C ₁₈ alkyl esters, including methyl, ethyl, propyl, isopropyl, butyl , isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and include stearyl, but not limited to), a straight-chain or alkenyl of C ₂ -C ₁₈ branched, ester (vinyl here, alkyl, undecenyl, and include linolenyl, but not limited to), cycloalkyl esters (cyclopropyl here the C ₃ -C _8, heptyl cyclobutyl, cyclopentyl, cyclohexyl, cyclohexane, and Including, but not limited to, cyclooctyl), ants Ruesters (including but not limited to phenyl, toluyl, xylyl, and naphthyl), alicyclic esters (including but not limited to menthyl), and aralkyl esters (here Includes, but is not limited to, benzyl and phenethyl).

  The term “pharmaceutically acceptable excipient” as used herein is selected for use, including any physiologically inert and pharmacologically inert substance known to those skilled in the art. That are compatible with the physical and chemical properties of the particular active ingredient. Pharmaceutically acceptable excipients include polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, cosolvents, buffer systems, surfactants, preservatives, sweeteners, Includes but is not limited to flavorings, pharmaceutical grade dyes and pigments. All or part of the pharmaceutically acceptable excipients contained in the pharmaceutical compositions described herein are used to create a film coating utilized in the new oral dosage forms described herein. Used for.

  The term “oral dosage form” as used herein means any pharmaceutical composition intended to be administered to the stomach from the mouth of an individual.

  As mentioned above, pharmaceutically acceptable excipients include polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, cosolvents, surfactants, preservatives, sweeteners, Includes but is not limited to flavorings, buffer systems, pharmaceutical grade dyes and pigments.

  A preferred solvent is water.

  Flavorings useful herein include those described in Non-Patent Document 2, which is incorporated herein by reference. Dyes or pigments useful herein include those described in Non-Patent Document 3, which is incorporated herein by reference.

  Preferred cosolvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycol.

  Preferred buffer systems include potassium acetate, boric acid, carbonic acid, phosphoric acid, succinic acid, malic acid, tartaric acid, citric acid, acetic acid, benzoic acid, lactic acid, glyceric acid, gluconic acid, glutaric acid, and glutamic acid. Systems include but are not limited to these. Particularly preferred buffer systems are phosphate, tartaric acid, citric acid, and potassium acetate buffer systems.

  Preferred surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters, and lanolin esters and ethers.

  Preferred preservatives include phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and their salts, boric acid and their salts, sorbic acid and their salts, chlorobutanol, benzyl alcohol, thimerosal, nitromersol, chloride This includes but is not limited to benzalkonium, cetylpyridinium chloride, methylparaben, and propylparaben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methylparaben, and propylparaben.

  Preferred sweetening agents include, but are not limited to, sucrose, glucose, saccharin, and aspartame. Particularly preferred are sucrose and saccharin.

  Preferred binders include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, carbomer, povidone, acacia, guar gum, xanthan gum, and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povidone, and sodium carboxymethylcellulose.

  Preferred fillers include but are not limited to lactose, sucrose, maltodextrin, mannitol, starch, and microcrystalline cellulose.

  Preferred plasticizers include, but are not limited to, polyethylene glycol, propylene glycol, dibutyl phthalate, castor oil, acetylated monoglycerides, and triacetin.

  Preferred lubricants include but are not limited to magnesium stearate, stearic acid, and talc.

  Preferred disintegrants include, but are not limited to, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, sodium carboxymethyl cellulose, alginic acid, clay, and ion exchange resin.

  Preferred polymers include hydroxypropylmethylcellulose (HPMC) alone and / or HPMC and hydroxypropylcellulose (HPC), carboxymethylcellulose, acrylic resin (eg, Eudragit® RL30D, manufactured by Rohm Pharma GmbH Weiderstadt (West Germany)), Methylcellulose, ethylcellulose, and polyvinylpyrrolidone, or other commercially available film coating preparations (eg, manufactured by Dri-Klear, Crompton & Knowles Corp., Mahwah, NJ), or Opadry, Colorcon, Westpoint, Pa. Manufacturing) combinations, but not limited to.

  Other formulations can be used to administer the bisphosphonate active ingredient. Such preparations include gel preparations described in Patent Document 2 and Patent Document 3, effervescent preparations described in Patent Document 4, iontophoretic preparations described in Patent Document 5, and Patent Documents 6 includes, but is not limited to, the transdermal formulation described in 6.

  The composition of the present invention can further enhance the flexibility of dosage and administration interval. For example, the compositions of the invention can be administered daily, weekly, biweekly, or monthly. A safe and effective amount will vary depending on the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, and the nature of the treatment being combined.

Claims (7)

A process for producing sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate comprising:
(A) supplying an aqueous solution of sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate;
(B) heating the aqueous solution;
(C) adding the alcohol to the aqueous solution, and (d) cooling the aqueous solution.   The method according to claim 1, wherein in the step (b), the aqueous solution is heated at a temperature of 25C to 75C.   The method according to claim 1 or 2, wherein in the step (d), the aqueous solution is cooled at a cooling rate of 0.06 ° C to 5 ° C / min. A process for producing sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate comprising:
(A) supplying an aqueous solution of sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate;
(B) heating the aqueous solution to 25-70 ° C;
(C) adding an alcohol to the aqueous solution at 25 to 70 ° C., and (d) cooling the aqueous solution with a gradient of 0.1 ° C. to 5 ° C./min. A process for producing sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate comprising:
(A) supplying an aqueous solution of sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate;
(B) heating the aqueous solution to 50-70 ° C;
(C) adding an alcohol to the aqueous solution at 50 to 70 ° C., and (d) cooling the aqueous solution with a gradient of 0.1 ° C. to 2 ° C./min. A process for producing sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate 2.5 hydrate comprising:
(A) supplying an aqueous solution of sodium 3-pyridyl-1-hydroxyethylidene-1,1-bisphosphonate;
(B) heating the aqueous solution to 50-70 ° C;
(C) adding an alcohol to the aqueous solution at 50 to 70 ° C., and (d) holding the aqueous solution at 50 to 70 ° C., and then cooling with a gradient of 0.1 ° C. to 2 ° C./min. A method characterized by that.   The method according to claim 1, wherein the alcohol is isopropanol.